Essentially pure acidic amine ligand aluminum complexes and their preparation

ABSTRACT

Essentially pure acidic amine ligand aluminum complexes useful as antacids are prepared by first reacting an acidic amine ligand with an aluminum alkoxide under anhydrous conditions to form an intermediate and further reacting the intermediate with water, these complexes are useful as antacids and as such in the treatment of hyperacidity.

This is a divisional of copending application Ser. No. 937,174, now U.S.Pat. No. 4,766,216, filed on Dec. 2, 1986.

FIELD OF THE INVENTION

This invention relates to essentially pure, acidic amine ligand aluminumcomplexes, their preparation and use as antacids in the treatment ofhyperacidity.

BACKGROUND OF THE INVENTION

Antacid preparations for oral administration and reduction of gastricacidity have long been known. Gastric antacids are generally classifiedas absorbable and nonabsorbable, depending on the amount of systemicabsorption of the cation responsible for the neutralization of gastrichydrochloric acid. The preferred gastric antacids are compounds whosecationic portion is not absorbed from the intestine and that raises thepH of the gastric contents only to about 5. This class of compounds isreferred to as nonabsorbable buffer antacids. Aluminum compounds aregenerally considered nonabsorbable. More recent studies, however,indicate at least some systemic aluminum absorption does occur. Aluminumcompounds have many of the desirable properties of an ideal bufferantacid. These include a good buffering ability, the absence of acidrebound and the absence of gas producing components. Nonaluminumantacids do not possess all of these desirable properties of aluminumcompounds and are therefore less desirable as antacids.

The effectiveness of aluminum containing antacids for the treatment ofpeptic ulcers has been clinically documented and is widely accepted.There are, however, certain side effects of using this type of antacidof which constipation is the most common.

Constipation results when aluminum inhibits contraction of the smoothmusculature delaying stomach emptying thus resulting in slight blockage.In addition, aluminum interacts in the intestine with anions such asphosphate and carbonate and forms insoluble compounds. The biologicalconsequences of the interaction of aluminum with phosphate following theintake of aluminum hydroxide are well known.

The primary event is precipitation of phosphate in the small intestineleading to elevated fecal phosphate. This reduces the availability ofphosphorus for systemic absorption and may lead to a lowering of serumphosphate levels. Because of the importance of phosphate, the body has aseries of homeostatic mechanisms to overcome this reduction in availablephosphate. Under conditions of normal phosphate levels, the input intoserum is balanced by its rate of removal. The sources of input areintestinal absorption, bone mineral resorption, renal phosphatereabsorption and transfer from soft tissue. Sources of removal includeintestinal secretion, bone mineralization, glomerular (kidney)filtration and transfer to soft tissue. When any one of these factors isperturbed, the other processes are modified to restore balance. Thus,when available phosphate decreases, processes such as bone resorptionand renal reabsorption increase considerably. The bone resorptionprocess, in addition to supplying phosphate, also resorbs calciumleading to elevated urinary calcium excretion. Thus, indirectly,aluminum interferes with calcium balance by causing calcium loss and ithas been suggested that the demineralization process may be acceleratedby aluminum.

The following clinical changes have been reported, in normal patients,in which the effects of aluminum on mineral metabolism have beenstudied.

1. Increase in fecal phosphorus and calcium.

2. Decrease in serum phosphorus.

3. Decrease in urinary phosphorus.

4. Increase in urinary calcium and magnesium.

5. Increase in renal reabsorption of phosphorus.

The combination of these biochemical perturbations is considered to be acontributing factor in bone loss.

A large number of commercial antacids are available which containaluminum compounds. Most of these products contain aluminum hydroxidealone or in combination with other basic compounds such as magnesiumhydroxide, calcium carbonate, sodium carbonate and the like. Otheraluminum containing compounds include aluminum phosphate, dihydroxyaluminum aminoacetate, aluminum carbonate, and magaldrate, a chemicalcombination of aluminum hydroxide and magnesium hydroxide. None of theseproducts overcome the undesirable mineral metabolic side effects ofaluminum containing antacids.

It would, therefore, be desirable to develop an antacid compositionhaving the advantageous properties of aluminum antacids while minimizingthe undesirable side effects.

SUMMARY OF THE INVENTION

A procedure for preparing essentially pure acidic amine ligand andaluminum complexes having the formula:

    Al(L)(OH).sub.2

wherein:

L is an acidic amine ligand

has been discovered. This has been achieved by first reacting analuminum alkoxide of the general formula Al(OR)₃ in the presence of ananhydrous solvent with an acidic amine ligand in an amount of from about0.5 mole to about 1 mole of acidic amine ligand per mole of aluminumalkoxide to form an intermediate.

Further reacting the intermediate with water in an amount of about 2moles per mole of aluminum alkoxide, the amount of acidic amine ligandand water being sufficient to replace all of the alkoxy groups of thealuminum alkoxide, removing the solvent and recovering the products.

DETAILED DESCRIPTION

In particular, it has been found that essentially pure acidic amineligand and aluminum complexes having an acid neutralization capacity ofat least 5 mEq/g and the formula:

    Al (L).sub.x (OH).sub.y

wherein:

X=1

Y=2 and

L is an acidic amine ligand

can be prepared.

The essentially pure acidic amine ligand and aluminum complexes of thepresent invention, have a high acid neutralization capacity (ANC), arefast acting, long lasting, pleasant tasting, easily formulated in solidor liquid dosage forms, have virtually no sodium content, andprecipitate less phosphate from the gastrointestinal (GI) tract thanaluminum hydroxide.

While the invention is not to be limited to theoretical considerations,it is believed that absorption of aluminum in the GI tract is lessenedby increasing the molecular size of the aluminum complex. In addition,it is believed that phosphate precipitation would be lessened bycomplexing the aluminum with appropriate acidic amine ligands so thatthe availability of aluminum for interaction with phosphate is reduced.

The aluminum alkoxide and acidic amine ligand are first reacted in theabsence of water in an anhydrous solvent to form an intermediate,further reacting the intermediate with water such that the amount ofacidic amine ligand and water being sufficient to replace all of thealkoxy groups of the aluminum alkoxide, removing the solvent andrecovering the product.

The stoichiometry of the reaction is believed to be as follows:

    Al(OR).sub.3 +xL→Intermediate                       1.

    Intermediate+yH.sub.2 O→Al(L).sub.x (OH).sub.y      2.

wherein

X=1

Y=2

L=an acidic amine ligand and

R=a carbon chain having 1 to about 8 carbon atoms.

Preferably the aluminum alkoxide is reacted in the presence of ananhydrous solvent with an acidic amine ligand in an amount of about 1mole of acidic amine ligand per mole of aluminum alkoxide to form anintermediate, and further reacting the intermediate with water in anamount of about 2 moles per mole of aluminum alkoxide, the amount ofacidic amine ligand and water being sufficient to replace all of thealkoxy groups of the aluminum alkoxide, removing the solvent andrecovering the product.

The aluminum alkoxide preferably has the formula Al(OR)₃, where R has acarbon chain of about 1 to about 8 carbon atoms. The chains may beeither straight or branched. Examples of such alkoxides are methoxide,ethoxide, isopropoxide, propoxide, butoxide, isobutoxide, amyloxide,hexoxide, octoxide, 2-ethyl-butoxide, 2-ethyl-hexoxide and the like. Thepreferred alkoxide is aluminum isopropoxide.

Throughout the specification, examples and claims, the term "acidicamine ligand" is defined as a carbon containing compound having at least3 carbon atoms and two or more donating atoms to provide strongcomplexation with aluminum at least one of which is a nitrogen and asecond an oxygen. The carbon containing compound can be in the form ofan alkane, alkene, cycloalkane, cycloalkene and aromatic hydrocarbon.The nitrogen atom can be in the form of an amine such as a primary,secondary, tertiary and heterocyclic amine. The oxygen atom is in theform of an acidic group such as a carboxylate and aromatic hydroxyl. Theacidic amine ligand may contain additional donating atoms such ascarboxylic, amino, aromatic hydroxyl and the like. Donating atoms arethose atoms which have an electron pair and act as a base whereas thealuminum atom accepts the electron pair and functions as an acid.

Acidic amine ligands useful in the present invention are illustrated bythe following nonlimiting list: iminodiacetic acid, hydroxyquinoline,and the like.

Exemplary essentially pure acidic amine ligand aluminum complexes areillustrated by the following non-limiting list: monoaluminumiminodiacetate, and monoaluminum hydroxyquinoline.

In a preferred embodiment, the aluminum alkoxide is reacted in thepresence of an anhydrous solvent with an acidic amine ligand in anamount of about 1 mole of acidic amine ligand per mole of aluminumalkoxide for about 30 to about 90 minutes at about 40° C. to about 90°C. to form an intermediate, then water is added dropwise in an amount ofabout 2 moles per mole of aluminum alkoxide, and the reactants heatedabout 30 minutes to about 2 hours at about 40° C. to about 90° C. Thereaction mixture is then cooled and the solvent removed.

The present invention also relates to the use of the essentially pureacidic amine ligand aluminum complexes as antacids and in the use ofsuch antacids in the treatment of hyperacidity.

The essentially pure acidic amine ligand aluminum complexes of thepresent invention have a high acid neutralization capacity (ANC) of atleast 5 mEq/g and a reduced interaction with phosphate in the GI tract.The acidic amine ligand aluminum complexes under simulated GI tractconditions are found to precipitate less than 20% of the availablephosphate while aluminum hydroxide wet gel is found to precipitate 63.4%of the available phosphate.

The acidic amine ligand aluminum complexes once prepared may be storedfor future use or formulated with conventional additives that ispharmaceutically acceptable carriers commonly used with antacidcompositions to form antacid compositions for oral ingestion. The acidicamine ligand aluminum complexes can be used alone or in combination withother active ingredients such as milk powders and milk fractions;antiflatulents such as simethicone; antacids such as magnesiumcarbonate, calcium carbonate, magnesium bicarbonate, calciumbicarbonate, sodium bicarbonate, aluminum hydroxide, aluminum phosphate,magnesium hydroxide, magnesium trisilicate, aluminum magnesiumtrisilicate hydrate, sodium aluminum silicate, calcium phosphates suchas mono, di and tribasic, ground limestone, ground oyster shells and thelike; plant extracts such as carrageenan, alginic acid and the like. Theacidic amine ligand aluminum complexes can be used in a method fortreating a physiological condition in a mammalian body that is benefitedfrom treatment with an antacid which comprises administering to saidmammalian body an antacid effective quantity of at least one acidicamine ligand aluminum complex alone or in combination with apharmaceutically acceptable carrier.

The antacid compositions may be prepared to offer a variety of texturesto suit particular applications. Such compositions may be in the form ofa lozenge, tablet, toffee, nougat, chewy candy, chewing gum, suspension,and so forth. The pharmaceutically acceptable carriers may be preparedfrom a wide range of materials. Without being limited thereto, suchmaterials include diluents, binders and adhesives, lubricants,disintegrants, colorants, bulking agents, flavorings, sweeteners andmiscellaneous materials such as buffers and adsorbents in order toprepare a particular antacid composition. The preparation ofconfectionery and chewing gum products is well known and does notconstitute an essential aspect of this invention.

As used herein, the term confectionery material means a productcontaining a bulking agent selected from a wide variety of materialssuch as sugar, corn syrup and in the case of sugarless bulking agentssugar alcohols such as sorbitol and mannitol and mixtures thereof.Confectionery material may include such exemplary substances aslozenges, tablets, toffee, nougat, chewy candy and so forth. In general,the bulking agent will comprise from about 5 to about 99% and preferablyabout 20 to about 95% by weight of the antacid confectionery product.

Lozenges are flavored dosage forms intended to be sucked and held in themouth. They may be in the form of various shapes, the most common beingflat, circular, octagonal and biconvex forms. The lozenge bases aregenerally in two forms, hard, boiled candy lozenges and compressedtablet lozenges.

The hard boiled candy lozenges are prepared from a mixture of sugar andother carbohydrates that are kept in an amorphous or glassy condition.This form can be considered a solid syrup of sugars generally havingfrom 0.5 to about 1.5% moisture. Such materials normally contain up toabout 92% corn syrup, up to about 70% sugar and from 0.1% to about 5.0%water. The syrup component generally is prepared from corn syrups highin dextrose, but may include other materials. Further ingredients suchas flavorings, sweeteners, acidulents, colorants and so forth may alsobe added.

Boiled candy lozenges may also be prepared from nonfermentable sugaralcohols such as sorbitol, mannitol, and hydrogenated corn syrup. Thecandy lozenges may contain up to about 95% sorbitol, a mixture ofsorbitol and mannitol at a ratio of about 9.5 to 0.5 up to about 7.5 to2.5 and hydrogenated corn syrup up to about 55% of the syrup component.

In contrast, compressed tablet lozenges contain particulate materialsand are formed into structures under pressure. They generally containsugars in amounts up to 95% and typical tablet excipients such asbinders and lubricants as well as flavors, colorants and so forth.

The lozenges may be made of soft confectionary materials such as thosecontained in nougat. These materials contain two primary components,namely a high boiling syrup such as corn syrup or the like, and arelatively light textured frappe, generally prepared from gelatin, eggalbumen, milk proteins such as casein, and vegetable proteins such assoy protein, and the like. The frappe is generally relatively light, andmay, for example, range in density from about 0.5 to about 0.7 g/cc. Bycomparison, the high boiling syrup, or "bob syrup," is relativelyviscous and possesses a higher density, and frequently contains asubstantial amount of sugar. Conventionally, the final nougatcomposition is prepared by the addition of the "bob syrup" to the frappeunder agitation, to form the basic nougat mixture. Further ingredientssuch as flavorings, oils, additional sugar and the like may be addedthereafter also under agitation. A general discussion of the compositionand preparation of nougat confections may be found in B. W. Minifie,CHOCOLATE, COCOA AND CONFECTIONERY: Science and Technology, 2nd edition,AVI Publishing Co., Inc., Westport, Connecticut, (1980), at 15 pages424-425, which disclosure is incorporated herein by reference.

Pharmaceutical suspensions of this invention may be prepared byconventional methods long established in the art of pharmaceuticalcompounding. Suspensions may contain conventional adjunct materialsemployed in formulating the suspensions of the art. The suspensions ofthe present invention can comprise:

(a) preservatives such as benzoic acid, sorbic acid, methylparaben,propylparaben and ethylenediaminetetracetic acid (EDTA). Preservativesare generally present in amounts up to about 1% and preferably fromabout 0.05 to about 0.5% by weight of the suspension;

(b) buffers such as citric acid-sodium citrate, phosphoric acid-sodiumphosphate, and acetic acid-sodium acetate in amounts up to about 1% andpreferably from about 0.05 to about 0.5% by weight of the suspension;

(c) suspending agents or thickeners such as cellulosics likemethylcellulose, carageenans like alginic acid and its derivatives,xanthan gums, gelatin, acacia, and microcrystalline cellulose in amountsup to about 20% and preferably from about 1% to about 15% by weight ofthe suspension;

(d) antifoaming agents such as dimethyl polysiloxane in amounts up toabout 0.2% and preferably from about 0.01 to about 0.1% by weight of thesuspension;

(e) sweeteners includes those sweeteners both natural and artificialwell known in the art. Sweetening agents such as monosaccharides,disaccharides and polysaccharides such as xylose, ribose, glucose,mannose, galactose, fructose, dextrose, sucrose, maltose, partiallyhydrolyzed starch or corn syrup solids and sugar alcohols such assorbitol, xylitol, mannitol and mixtures thereof may be utilized inamounts from about 10% to about 60% and preferably from about 20% toabout 50% by weight of the suspension. Water soluble artificialsweeteners such as saccharin and saccharin salts such as sodium orcalcium, cyclamate salts, acesulfame-K, aspartame and the like andmixtures thereof may be utilized in amounts from about 0.001% to about5% by weight of the suspension;

(f) flavorants include both natural and artificial flavors, and mintssuch as peppermint, menthol, vanilla, artificial vanilla, chocolate,artificial chocolate, cinnamon, various fruit flavors, both individualand mixed may be utilized in amounts from about 0.5% to about 5% byweight of the suspension;

(g) colorants useful in the present invention include pigments which maybe incorporated in amounts of up to about 6% by weight of thecomposition. A preferred pigment, titanium dioxide, may be incorporatedin amounts up to about 1%. Also, the colorants may include other dyessuitable for food, drug and cosmetic applications, and known as F.D. &C. dyes and the like. Such dyes are generally present in amount up toabout 0.25% and preferably from about 0.05% to about 0.2% by weight ofthe suspension;

(h) decolorizing agents such as sodium metabisulfite, ascorbic acid andthe like may be incorporated into the suspension to prevent colorchanges due to aging. In general, amounts up to about 0.25% andpreferably 0.05% to 0.2% by weight of the suspension are used;

(i) solubilizers such as alcohol, propylene glycol, polyethylene glycoland the like may be used to solubilize the flavors. Solubilizing agentsare generally present in amounts up to about 10%; preferably from about2% to about 5% by weight of the suspension.

Pharmaceutical suspensions of the present invention may be prepared asfollows:

(A) admixing the thickener with water heated from about 40° C. to about95° C. preferably about 40° C. to about 70° C. to form a dispersion ifthe thickener is not water soluble or a solution if the thickener iswater soluble,

(B) admix the sweetener with water to form a solution,

(C) admix the acidic amine ligand aluminum complex with thethickener-water admixture to form a uniform thickener-adsorbatecomposition,

(D) combine the sweetener solution with the thickner-adsorbatecomposition and mix until uniform.

(E) admix optional ingredients such as colorants, flavors, decolorants,solubilizers, antifoaming agents, buffers and additional water with themixture of step (D) to form the suspension.

Pharmaceutical tablets of this invention may also be in chewable form.This form is particularly advantageous because of convenience andpatient acceptance. To achieve acceptable stability and quality as wellas good taste and mouth feel several considerations are important,namely amount of active substance per tablet, flavor, compressibilityand organoleptic properties of the acidic amine ligand aluminum complex.

The preparation of chewable medicated candy is by procedures similar tothose used to make soft confectionery products. This procedure generallyinvolves the formation of a boiled sugar-corn syrup blend to which isadded a frappe mixture. The boiled sugar-corn syrup blend may beprepared from sugar and corn syrup blended in parts by weight ratio ofabout 90 to 10 to about 10 to 90. This blend is heated to temperaturesabove 121° C. to remove water and to form a molten mass. The frappe isgenerally prepared from gelatin, egg albumen, milk proteins such ascasein, and vegetable proteins such as soy protein, and the like whichare added to a gelatin solution and rapidly mixed at ambient temperatureto form an aerated sponge like mass. The frappe is then added to themolten candy base and mixed until homogenous at temperatures between 65°C. and 121° C.

The acidic amine ligand aluminum complex can then be added as thetemperature of the mix is lowered to about 65° C. to about 135° C.whereupon additional ingredients are added such as flavors, andcolorants. The formulation is further cooled and formed to pieces ofdesired dimensions.

A general discussion of the lozenge and chewable tablet forms ofconfectionary may be found in H. A. Lieberman and L. Lachman,Pharmaceutical Dosage Forms: Tablets Volume 1, Marcel Dekker, Inc., NewYork, N.Y., 1980, at pages 289 to 466 which disclosure is incorporatedherein by reference.

As used herein, the term chewing gum product means a product containinga chewing gum formulation. In general, the chewing gum formulation willcomprise from about 5 to about 99% and preferably 20% to about 95% byweight of the acidic amine ligand aluminum complex chewing gum product.

With regard to a chewing gum formulation, such formulations contain agum base and various additives, such as sweeteners and flavors. The gumbase employed will vary greatly depending on various factors such as thetype of base used, consistency desired and other components used to makethe final product. In general, amounts of about 5% to about 45% byweight of the final chewing gum composition are acceptable for use inchewing gum compositions with preferred amounts of about 15% to about25% by weight. The gum base may be any water-insoluble gum base wellknown in the art. Illustrative examples of suitable polymers in gumbases include both natural and synthetic elastomers and rubbers. Forexample, those polymers which are suitable in gum bases, include,without limitation, substances of vegetable origin such as chicle,jelutong, gutta percha and crown gum. Synthetic elastomers such asbutadiene-styrene copolymers, isobutylene-isoprene copolymers,polyethylene, polyisobutylene and polyvinylacetate and mixtures thereof,are particularly useful.

The gum base composition may contain elastomer solvents to aid insoftening the elastomer component. Such elastomer solvents may comprisemethyl, glyceryl orpentaerythrityl esters of rosins or modified rosins,such as hydrogenated, dimerized or polymerized rosins or mixturesthereof. Examples of elastomer solvents suitable for use herein includethe pentaerythrityl ester of partially hydrogenated wood rosin,pentaerythrityl ester of wood rosin, glyceryl ester of wood rosin,glyceryl ester of partially dimerized rosin, glyceryl ester ofpolymerized rosin, glyceryl ester of tall oil rosin, glyceryl ester ofwood rosin and partially hydrogenated wood rosin and partiallyhydrogenated methyl ester of rosin, such as polymers of alpha-pinene andbeta-pinene; terpene resins including polyterpene and mixtures thereof.The solvent may be employed in an amount ranging from about 10% to about75% and preferably about 45% to about 70% by weight to the gum base.

A variety of traditional ingredients such as plasticizers or softenerssuch as lanolin, stearic acid, sodium stearate, potassium stearate,glyceryl triacetate, glycerine and the like as well as natural andsynthetic waxes, petroleum waxes, such as polyurethane waxes, paraffinwaxes and microcrystalline waxes may also be incorporated into the gumbase to obtain a variety of desirable textures and consistencyproperties. These individual additional materials are generally employedin amounts of up to about 30% by weight and preferably in amounts fromabout 3% to about 20% by weight of the final gum base composition.

The chewing gum composition may additionally include the conventionaladditives of flavoring agents, coloring agents such as titanium dioxide,emulsifiers such as lecithin and glyceryl monostearate; and additionalfillers such as aluminum hydroxide, alumina, aluminum silicates, calciumcarbonate, and talc and combinations thereof. These fillers may also beused in the gum base in various amounts. Preferably the amount offillers when used will vary from about 4% to about 30% by weight of thefinal chewing gum.

In the instance where auxiliary sweeteners are utilized, the presentinvention contemplates the inclusion of those sweeteners well known inthe art, including both natural and artificial sweeteners. Thus,additional sweeteners may be chosen from the following non-limitinglist:

A. Water-soluble sweetening agents such as monosaccharides,disaccharides and polysaccharides such as xylose, ribose, glucose,mannose, galactose, fructose, dextrose, sucrose, maltose, partiallyhydrolyzed starch, or corn syrup solids and sugar alcohols such assorbitol, xylitol, mannitol and mixtures thereof.

B. Water-soluble artificial sweeteners such as the soluble saccharinsalts, i.e., sodium, or calcium saccharin salts, cyclamate salts,acesulfame-K and the like, and the free acid form of saccharin.

C. Dipeptide based sweeteners such as L-aspartyl-L-phenylalanine methylester and materials described in U.S. Pat. No. 3,492,131 and the like.In general, the amount of sweetener will vary with the desired amount ofsweeteners selected for a particular chewing gum. This amount willnormally be 0.001% to about 90% by weight when using an easilyextractable sweetener. The water-soluble sweeteners described incategory A above, are preferably used in amounts of about 25% to about75% by weight, and most preferably from about 50% to about 65% by weightof the final chewing gum composition. In contrast, the artificialsweeteners described in categories B and C are used in amounts of about0.005% to about 5.0% and most preferably about 0.05% to about 2.5% byweight of the final chewing gum composition. These amounts areordinarily necessary to achieve a desired level of sweetness independentfrom the flavor level achieved from flavor oils. While water may beadded independently with dry sweeteners, it will generally be added aspart of a corn syrup or corn syrup mixture.

Suitable flavorings include both natural and artificial flavors, andmints such as peppermint, menthol, artificial vanilla, cinnamon, variousfruit flavors, both individual and mixed, and the like are contemplated.The flavorings are generally utilized in amounts that will varydepending upon the individual flavor, and may, for example, range inamounts of about 0.5% to about 3% by weight of the final composition.

The colorants useful in the present invention, include the pigmentswhich may be incorporated in amounts of up to about 6% by weight of thecomposition. A preferred pigment, titanium dioxide, may be incorporatedin amounts of up to about 1% by weight. Also, the colorants may includeother dyes suitable for food, drug and cosmetic applications, and knownas F.D. & C. dyes and the like. The materials acceptable for theforegoing spectrum of use are preferably water-soluble. Illustrativeexamples include the indigo dye, known as F.D. & C. Blue No. 2, which isthe disodium salt of 5,5-indigotindisulfonic acid. Similarly, the dyeknown as F.D. & C. Green No. 1, comprises a triphenylmethane dye and isthe monosodium salt of4-[4-N-ethyl-p-sulfo-benzylamino)diphenylmethylene]-[1-(N-ethyl-N-p-sulfonium-benzyl)-2,5-cyclohexadienimine].A full recitation of all F.D. & C. and D. & C. colorants and theircorresponding chemical structures may be found in the Kirk-OthmerEncyclopedia of Chemical Technology, 3rd Edition, in Volume 6, at pages561-595, which text is accordingly incorporated herein by reference.

Suitable oils and fats that are usable would include partiallyhydrogenated vegetable or animal fats, such as coconut oil, palm kerneloil, beef tallow, lard, and the like. These ingredients are generallyutilized in amounts with respect to the comestible product of up toabout 7.0% by weight, and preferably up to about 3.5% by weight of thefinal product.

The quantity of acidic amine ligand aluminum complex used may varywidely depending upon the particular complex, its ANC and the desiredANC of the pharmaceutical product. Amounts of acidic amine ligandaluminum complex of about 200 to about 6,000 mg per dosage are useabledependent upon the particular complex.

The dosage range of the hydroxyquinoline aluminum complex would be about375 to about 2,250 mg per dose. The dosage range of the iminodiaceticacid aluminum complex would be about 720 to about 4,400 mg per dose.

The present invention is further illustrated by the following examples.All parts and percentages in the examples and throughout thespecification and claims are by weight of the final composition unlessotherwise indicated.

EXAMPLE 1

This Example demonstrates the formation of acidic amine ligand aluminumcomplexes of this invention.

The following procedure was followed to prepare each of the acidic amineligand aluminum complexes listed in Tables 1 and 2.

To a solution of aluminum isopropoxide containing 1/2 mole of aluminumisopropoxide in 500 ml of anhydrous isopropanol under nitrogen at 80° C.was added 1/2 mole of acidic amine ligand with mixing. The mixture wasthen maintained at 80° C. for one hour. One mole of water was then addeddropwise to the solution with mixing and the mixture maintained anadditional 1.5 hours at 80° C. The reaction mixture was then cooled andthe solvent removed by distillation at reduced pressure at a temperatureless than 60° C. to yield a white powder.

                                      TABLE 1                                     __________________________________________________________________________    ANC AND MOLECULAR WEIGHT FOR                                                  INVENTIVE ACIDIC AMINE LIGAND ALUMINUM COMPLEXES                                                                           MOLECULAR                        COMPLEX                                                                              POLYALCOHOL                                                                             Al:L ANC (MEQ/G)  ANC (EQ/MOLE)                                                                           WEIGHT OF                        NUMBER LIGAND (L)                                                                              RATIO                                                                              LIGAND                                                                              COMPLEX                                                                              COMPLEX   COMPLEX                          __________________________________________________________________________    1      IDA       1.1  -4.97  6.76  1.44      212.5                            2      HQ        1:1   7.81 13.23  2.81      212.5                            __________________________________________________________________________     In tables 1, 2 and 3.                                                         IDA = Iminodiacetic acid                                                      HQ = Hydroxyquinoline                                                    

                                      TABLE 2                                     __________________________________________________________________________    ROSSETT-RICE AND pH STAT DATA FOR                                             INVENTIVE ACIDIC AMINE LIGAND ALUMINUM COMPLEXES                                              ROSSETT-RICE        pH STAT                                   COMPLEX                                                                              ACIDIC AMINE                                                                           Al:L LAG PEAK                                                                              RR     (MINUTES)                                 NUMBER LIGAND (L)                                                                             RATIO                                                                              (MIN)                                                                             PH  TIME (MIN)                                                                           T50 T90                                   __________________________________________________________________________    1      IDA      1:1  --  --  --     --                                        2      HQ       1:1  0.0 4.05                                                                              52.0   0.6 1.5                                   __________________________________________________________________________

The acidic amine ligand aluminum complexes have ANC value of from about7 to about 13 in mEq/g. Aluminum hydroxide dry gel has an ANC of about22 to 30 mEq/g and 2.2 to 2.9 Eq/mole. The method of preparation ofaluminum hydroxide gel greatly effects its ANC and this accounts for thevariation in test results. Complexes having an ANC greater than 5 mEq/gare suitable for use as antacids. The inventive acidic amine ligandaluminum complexes of this Example all have an acceptable ANC.

Procedures

The molecular weight for each complex given in Table I was calculated byassaying the aluminum content for each complex then assuming onealuminum atom per molecule for complexes 1 and 2.

Acid Neutralizing Capacity (ANC)

Test Preparation: (ANC TEST<301>, p. 1192, USPXXI, Mack Pub. Co.,Easton, Pa., 1984).

Transfer an accurately weighed portion of test substance to a 250 mlbeaker, add 70 ml of water, and mix for 1 minute.

Procedure:

Pipet 30.0 mL of 1.0N hydrochloric acid volumetric solution into theTest Preparation while continuing to stir with the Magnetic Stirrer.Stir for 15 minutes, accurately timed, after the addition of the acid,begin to titrate immediately, and in a period not to exceed anadditional 5 minutes, titrate the excess hydrochloric acid with 0.5Nsodium hydroxide volumetric solution to attain a stable (for not lessthan 15 seconds) pH of 3.5. Calculate the number of mEq of acidconsumed, and express the result in terms of mEq of acid consumed per gof the substance tested. Each mL of 1.0N hydrochloric acid is equal to 1mEq of acid consumed.

The ANC is a static test which gives only a limited picture of theantacid behavior. Complexes were then tested for buffering capacity bythe Rossett-Rice titration method and for their rate of reactivity bythe pH-stat titration. These two tests are dynamic and give a moreprecise picture of antacid reactivity.

Briefly, the Rossett-Rice (RR) titration, N. E. Rossett, M. L. Rice,Gastroenterology, 1954, 26, 490, involves the addition of acid at aconstant rate to a quantity of antacid equivalent to 26.4 mEq of ANC andmonitoring the pH as a function of time. Three parameters whichcharacterize the antacid are obtained. These are the lag time, duration(RR time) and peak pH. The lag time is the time, in minutes required forthe reaction mixture to reach pH3. The RR time is the time, in minutes,the reaction mixture remains above pH3. The peak pH is the maximum pH ofthe reaction mixture during the test. The pH-stat titration, N. J.Kerkoff, et al., J. Pharm. Sci., 1977, 66, 1528, requires the variableaddition of acid to the antacid sample (equivalent to 2 mEq of ANC) at arate sufficient to maintain the pH at 3. This data is then plotted asthe volume of acid added versus time. From this plot one can obtain twoparameters which characterize the reactivity of the antacid. These areT₅₀ and T₉₀ which are the times required to neutralize 50% and 90% ofthe total theoretical amount of acid. The data for both tests ispresented in Table 2 and shows several interesting trends. First, allcomplexes tested show good to excellent pH-stat results with T₅₀ 's ofless than 3 minutes and T₉₀ 's of less than 20 minutes. The RR data alsoshow excellent results for all complexes. They react immediately withacid (lag time=O), show good buffering ability and remain above pH 3.0(RR time) for 30 minutes or more.

EXAMPLE 2

This Example demonstrates decreased phosphate interaction of inventiveacidic amine ligand aluminum complexes when compared to aluminumhydroxide wet gel.

The acidic amine ligand aluminum complexes in Table 3 are the samecomplexes prepared and tested in Example 1.

                  TABLE 3                                                         ______________________________________                                        Phosphate Interaction of Inventive Acid Amine Ligand                          Aluminum Complexes and Aluminum Hydroxide Wet Gel.                            Complex                                                                              Polyalcohol Ratio   Phosphate                                          Number Ligand (L)  Al:L    Remaining (%)                                      ______________________________________                                        1      IDA         1:1     99.6                                               2      HQ          1:1     80.3                                               Aluminum hydroxide wet gel                                                                       36.6                                                       ______________________________________                                    

The amount of phosphate remaining in solution after treatment with acidfollowed by intestinal fluid was determined and the results aresummarized in Table 3. A range, from 19.7% to 0.4% of added phosphate,was removed from the solution by the tested compounds. Aluminumhydroxide wet gel removed 63% of the phosphate added. All of thecompounds tested showed improvements over aluminum hydroxide in terms ofnot precipitating phosphate; i.e., more than 80% of the added phosphateremained in the solution. Aluminum hydroxide wet gel, the major activeingredient in many commercially available antacid preparations, was usedas a reference. This gel reacts with hydrochloric acid in the stomach toproduce water soluble aluminum chloride which undergoes subsequenthydrolysis to form a hydrated hydroxy aluminum complex. In the smallintestine, this aluminum complex reacts with dietary phosphate to formwater insoluble phosphate salts. In order to examine the phosphateinteraction properties of the inventive compounds as they pass throughthe gastrointestinal tract, all compounds were subjected to reactionwith hydrochloric acid (physiological acid strength) before reactingwith phosphate.

The Rossett-Rice titration was used to condition each of the compoundsbefore reaction with phosphate. This titration attempts to simulatein-vivo stomach conditions and is one of the most common in-vitromethods for evaluating the effectiveness of an antacid formulation.Different antacids vary markedly in their in vivo and in vitro potencyand it has therefore been recommended that antacid dosage be determinedaccording to milliequivalents of neutralizing capacity rather thanvolume or number of tablets of different antacids. A standardized sampleweight of 3.6 g was used in this study. The experimental method is asfollows:

A pourable slurry containing 3.6 g of the test compound was introducedinto an acidic solution of pH about 1.6 at 37° C.

Simultaneously, 0.1N HCl was added at a constant rate of 4 mL/min for 15minutes. The period of fifteen minutes is the gastric residence timesuggested by the OTC panel, Federal Register #65, 1973, 38, 8717. Afterreaction with acid, the mixture was treated with intestinal fluid T.S.(pH=7.5) which is 0.05M in phosphate. The amount of intestinal fluidadded was calculated to deliver one mole of phosphate per mole ofaluminum. The pH of the suspension was constantly monitored and it wasobserved that, for certain compounds, the mixture remained very acidicafter the intestinal fluid was added. In order to simulate in vivoconditions, 1.0N sodium hydroxide was added to bring the pH of the finalsuspension to 7.0.

The suspension was stirred for 15 minutes and then centrifuged. Analiquot of the supernatant was analyzed for phosphate and the amount ofphosphate remaining in solution was calculated.

The amount of phosphate remaining in solution is summarized in Table 3above.

The invention being thus described, it will be obvious that the same maybe varied in many ways. Such variations are not to be regarded as adeparture from the spirit and scope of the invention and all suchmodifications are intended to be included within the scope of thefollowing claims.

We claim:
 1. A method for treating a physiological condition in amammalian body that is benefited from treatment with an antacid whichcomprises administering to said mammalian body an antacid effectivequantity of at least one essentially pure complex of an acidic amineligand and aluminum having the formula:

    Al(L).sub.x (OH).sub.y

wherein: L is an acidic amine ligand having at least 3 carbon atoms andtwo donating atoms at least one of which is a nitrogen and a second anoxygen, said oxygen atom is in the form of an acidic group; and x=1 andy=2, wherein the acidic amine ligand is selected from the groupconsisting of iminodiacetic acid, and hydroxyquinoline.
 2. A method inaccordance with claim 1 wherein the antacid complex is administeredorally.
 3. A method in accordance with claim 1 wherein the physiologicalcondition is or is accompanied by hyperacidity.
 4. An antacidcomposition comprising:(a) an antacid effective quantity of at least oneessentially pure complex of a acidic amine ligand and aluminum havingthe formula:

    Al(L).sub.x (OH).sub.y

wherein: L is an acidic amine ligand having at least 3 carbon atoms andtwo donating atoms at least one of which is a nitrogen and a second anoxygen, said oxygen atom is in the form of an acidic group; and x=1 andy=2, wherein the acidic amine ligand is selected from the groupconsisting of iminodiacetic acid, and hydroxyquinoline and (b) apharmaceutically acceptable carrier.
 5. The antacid composition of claim4 wherein the essentially pure acidic amine ligand and aluminum complexhas an acid neutralization capacity of at least 5 mEq/g and the molarratio of acidic amine ligand to aluminum in the complex is about 1:1. 6.A method for treating a physiological condition in a mammalian body thatis benefited from treatment with an antacid which comprisesadministering to said mammalian body an antacid effective quantity ofthe composition of claim
 4. 7. A method in accordance with claim 6wherein the antacid composition is administered orally.